P1474: HEMOLYTIC MARKERS, MORTALITY, AND THROMBOEMBOLIC EVENTS IN CAD: RISK ASSESSMENT BY TIME PERIOD SINCE DIAGNOSIS
Authors: Quentin A Hill, Wilma Barcellini, Alexander Röth, Alia Karaouni, Marion Afonso, Yoo Ronnie, Julien Tanniou, Julien Rubio, Catherine M Broome
Journal: HemaSphere (2023)

Topic: 28. Enzymopathies, membranopathies and other anemias Background: Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia. Although there is consensus on an increased risk of thromboembolic events (TEs) in patients with CAD than those without CAD, the evidence on mortality is mixed and the association of both risks with the time since disease diagnosis and biomarker levels has been rarely assessed. Aims: This study evaluated whether patients with CAD have higher risk of mortality and TEs compared with a matched non-CAD population at various time periods since diagnosis. The association between biomarker levels (hemoglobin [Hb], bilirubin, and lactate dehydrogenase [LDH]) and the risk of mortality and TEs in CAD patients was also assessed. Methods: This was a retrospective, cohort study of CAD patients and exact-matched non-CAD patients in the US, identified using the OPTUM® de-identified Electronic Health Record dataset (2007-2021). Mortality and TEs were assessed over the full follow-up period (till the end of medical activity, study period, or death) and at pre-defined time periods (100 days, 1 year, 2 years, 3 years, 5 years, and 10 years) from CAD diagnosis. Biomarker levels were assessed during follow-up, and categorized as follows: bilirubin: severe, >2.4 mg/dL; moderate, >1.2─≤2.4 mg/dL; normal, ≤1.2 mg/dL, LDH: severe, >500 U/L; moderate, >250─≤500 U/L; normal, ≤250 U/L, Hb: no anemia, Hb ≥12 g/dL; mild, Hb ≥10─<12 g/dL; moderate, Hb ≥8─<10 g/dL; and severe, Hb <8 g/dL. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CI) were obtained for the pre-defined time periods using multivariate cox proportional hazards regression analyses. Time-varying cox regressions were used in the CAD cohort to analyze the association between biomarkers (all observations until event) and risk of mortality or TE. Results: Overall, 457 patients with CAD and 2285 exact-matched non-CAD patients were included. The mortality and TE risks in CAD compared with non-CAD cohorts were significantly higher, particularly in the early periods after diagnosis (e.g., 100 day aHR [95% CI], mortality: 16.36 [6.83─39.19]; TE: 4.92 [3.22─7.45]; both P<0.001) compared with longer periods (e.g., 10 year aHR [95% CI], mortality: 2.26 [1.84─2.77]; TE: 2.08 [1.71─2.53]; both P<0.001) (Table 1). In the CAD cohort, patients with mild, moderate, or severe anemia had significantly higher risk of mortality than those without anemia (mild: aHR [95% CI]: 2.55 [1.40─4.65]; P=0.002; moderate: 7.00 [4.00─12.23]; and severe: 16.70 [9.14─30.34]; both P=0.001). Moderate and severe anemia were also correlated with higher risk of TEs compared with no anemia (aHR [95% CI]: 2.16 [1.28─3.64]; P=0.004 and 3.37 [1.81─6.26]; P=0.001, respectively). Severe bilirubin (aHR [95% CI]: 3.03 [1.98─4.64]; P=0.001) and severe LDH levels (aHR [95% CI]: 2.31 [1.29─4.13]; P=0.005) were associated with increased risk of mortality compared with normal levels. Summary/Conclusion: The clinical burden associated with CAD is significant and extends beyond anemia. Patients with CAD were twice more likely to die or experience TEs than those without CAD. These risks were particularly high in the early periods after diagnosis with mortality risk 16 times and TE risk 5 times higher in the first 100 days. Within the CAD cohort, severely deranged markers of hemolysis (LDH, bilirubin) and anemia were associated with increased mortality risk. Moderate and severe anemia were also associated with increased TE risk. Early and chronic control of complement activation and the resulting hemolysis in CAD may therefore help manage the risk of mortality and TEs.Keywords: Thromboembolic events, AIHA (see autoimmune hemolytic anemia), Hemoglobin, Mortality